It is widely accepted that the existing clinical paradigm of one treatment fits all is a major factor in the lack of progress in the effective treatment of a highly heterogeneous diseases. We propose a new innovative clinical paradigm that optimizes brain cancer therapy using patient-specific markers of therapeutic response. Our long-term objective is to improve survival in brain tumor (glioblastoma multiforme) patients by utilizing a powerful and ultra-sensitive technology, Accelerator Mass Spectrometry (AMS). Our approach follows these three steps: 1) Quantify tumor exposure to chemotherapy in individual patients at the earliest stages of therapy; 2) Quantify tumor-level response to treatment in individual patients by developing validated biomarkers of therapeutic efficacy; 3) Optimize each patient's treatment by adjusting dose, dose schedule, or by placing the patient on a different course of therapy. Currently, laboratory methods enabling this approach are only partially developed. Our plan is to fully develop and validate innovative laboratory techniques and demonstrate their performance in cell and animal models. Once their feasibility has been demonstrated, we will employ these techniques in future clinical studies of brain cancer patients. Our specific aims in this Phase I proposal are to: 1) develop and optimize HPLC/AMS analytical methods for quantifying tissue-level [14C]- temozolomide (temador) concentration; 2) develop methodologies for quantifying potential biomarkers of therapeutic efficacy in tumor tissue; and 3) establish assay sensitivity experimentally and demonstrate the feasibility of this technique in support of trials conducted in patients. These clinical trials will characterize, for the first time, the inter-patient variability in tumor temozolomide exposure, relate that exposure to quantitative markers of therapeutic efficacy, and characterize the correlation between these measures and patient outcome. Ultimately, our goal is develop a tool physicians can use to safely and quickly establish patient- specific strategies for treatment of brain cancer patients. This proposal lays the groundwork for physicians to employ powerful new technologies to improve brain tumor treatment and prolong patient survival. PUBLIC HEALTH RELEVANCE: The proposed effort will validate approaches that change the current paradigm of one-chemotherapy-treatment-fits-all to a personalized chemotherapy approach that is based on the patient's individual response to the treatment. This approach may be adapted to other types of cancers, and with further development, may have far reaching benefits that affect an even greater number of patients. [unreadable] [unreadable] [unreadable]